Yu Fu-Lin, Zhang Ming-Yan, Song Gang-Wei, Ning Yang-Shan, Wu Xian, Gao Yan
Department of Cardiovascular Medicine, Xi'an Trade Union Hospital, Xi'an, Shaanxi Province, China.
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States of America.
PLoS One. 2025 May 29;20(5):e0320557. doi: 10.1371/journal.pone.0320557. eCollection 2025.
Arsenic can enter the human body through environmental exposure via food, drinking water, and chemotherapy for cancer. Prolonged and excessive exposure to arsenic causes various toxic reactions, leading to diseases that significantly impact health and lifespan. Increasing evidence suggests that arsenic damages skeletal muscle tissue by reducing muscle mass and causing atrophy, thereby contributing to conditions such as respiratory and cardiovascular diseases, as well as diabetes. Fatty acid β-oxidation is the most efficient mechanism for ATP production and serves as a primary energy source for tissues, including the heart and skeletal muscles. However, the metabolic mechanisms underlying arsenic's effects on muscle function and pathogenesis remain incompletely understood. In this study, we investigated the role of mitochondrial fatty acid oxidation in arsenic-induced muscular damage using mouse skeletal muscle C2C12 cells. Our results demonstrated a dose-dependent inhibitory effect of sodium arsenite (0-2 µM, 72 hours) on C2C12 cells proliferation, viability, and differentiation (indicated by reduction of myogenic differentiation 1 mRNA expression). Arsenic exposure disrupted mitochondria through increasing reactive oxygen species production, reducing mitochondrial membrane potential to 16.45%, downregulating mitochondrial fatty acid metabolism-related enzymes (carnitine palmitoyltransferase 1B to 15.05% and choline kinase beta mRNA to 49.94%), and decreasing mitochondrial DNA copy number to 42.08%. These findings suggest that arsenic-induced pathological changes in skeletal muscle are associated with impaired mitochondrial membrane function, disrupted fatty acid metabolism, and reduced mitochondrial DNA content in muscle cells.
砷可通过食物、饮用水等环境暴露途径以及癌症化疗进入人体。长期过量接触砷会引发各种毒性反应，导致对健康和寿命有重大影响的疾病。越来越多的证据表明，砷通过减少肌肉量和导致萎缩来损害骨骼肌组织，从而引发诸如呼吸和心血管疾病以及糖尿病等病症。脂肪酸β-氧化是产生三磷酸腺苷（ATP）最有效的机制，并且是包括心脏和骨骼肌在内的组织的主要能量来源。然而，砷对肌肉功能和发病机制影响的代谢机制仍未完全了解。在本研究中，我们使用小鼠骨骼肌C2C12细胞研究了线粒体脂肪酸氧化在砷诱导的肌肉损伤中的作用。我们的结果表明，亚砷酸钠（0 - 2 μM，72小时）对C2C12细胞增殖、活力和分化具有剂量依赖性抑制作用（通过肌源性分化1 mRNA表达降低来表明）。砷暴露通过增加活性氧的产生破坏线粒体，将线粒体膜电位降低至16.45%，下调线粒体脂肪酸代谢相关酶（肉碱棕榈酰转移酶1B降至15.05%，胆碱激酶β mRNA降至49.94%），并将线粒体DNA拷贝数降低至42.08%。这些发现表明，砷诱导的骨骼肌病理变化与线粒体膜功能受损、脂肪酸代谢紊乱以及肌肉细胞中线粒体DNA含量减少有关。
